Summary: Recruitment to date remains strong within the Vasculitis Natural History Study. All patients seen at the NIH Clinical Center receive comprehensive clinical evaluation and contribute samples to a growing biobank. Over the last year, we have focused on three forms of vasculitis: large vessel vasculitis (LVV), relapsing polychondritis (RP, and deficiency of adenosine deaminase 2 (DADA2). We have currently evaluated >500 patients with vasculitis under an observational protocol (14-AR-0200) and continue to see approximately 100 new patients each year in addition to following selected patients over time. Since the time of the last report we have firmly established a vascular imaging program to determine the ttility of dmaging as a disease activity biomarker in LVV. A goal of the VTRP is to find novel ways to characterize vasculitis using advanced molecular imaging and genomic approaches. Giant cell arteritis (GCA) and Takayasus arteritis (TAK) are the two major forms of large-vessel vasculitis (LVV), defined by inflammation of the aorta and primary branches. Clinical assessment of disease activity in LVV can be challenging, thus posing a barrier to effective monitoring and treatment. Patients with LVV can develop new vascular lesions during periods of apparent sustained clinical remission and with normal inflammatory markers. While several studies have examined the potential of molecular imaging in LVV, the role of FDG-PET to detect vascular inflammation, monitor disease activity over time, and predict clinical outcomes remains unclear. To date, we have comprehensive imaging and clinical data from 356 study visits collected in 56 patients with GCA, 55 patients with TAK, and 60 controls which is the largest prospective dataset of its kind in LVV, and we continue to recruit 4-8 new patients with these conditions each month. Because we use low-radiation protocols and MR-based technology, we have been able to include pediatric patients with TAK in these studies, a rare but important subgroup of patients who are often excluded from ongoing clinical research. Over the last year, we have showed that FDG-PET provides information about vascular inflammation that is at times contradictory to clinical assessment in LVV. While most patients with clinically active vasculitis had FDG-PET scan findings that demonstrate concordant vascular inflammation, the majority of patients in clinical remission (41 of 71, 58%) also had evidence of ongoing vascular inflammation by PET. We developed a novel qualitative scoring system to assess the degree of inflammation on PET, which we named the PET Vascular Activity Score (PETVAS). We used PETVAS to show that degree of vascular PET activity during clinical remission predicted future clinical relapse in our cohort, highlighting the prognostic utility of advanced molecular imaging in these conditions. In a second related study, we examined to what extent magnetic resonance angiography (MRA) provided unique versus redundant information about vascular disease compared to FDG-PET. Since FDG-PET is rarely available in the United States, outside its accepted use in oncology, we wanted to compare performance characteristics of PET versus MRA to assess vascular disease activity and extent. We found that investigators agreed on the interpretation of vascular activity between MRA and FDG-PET in 90 out of 133 paired studies (68%). However, only PET and not MRA was significantly associated with clinical assessment of disease activity, suggesting that PET is a better marker of vascular inflammation than MRA. Edema and wall thickness on MRA were independently associated with PET activity, which could enable the use of MRA as a potential surrogate when access to PET is not available. In contrast to the assessment of vascular inflammation, MRA was better suited than PET to detect and categorize the extent of vascular damage. We have also firmly established a new research initiative in relapsing polychondritis. Relapsing polychondritis is a multisystem, rheumatologic disease characterized by inflammation of cartilaginous structures including the ear, nose, joints and airways. There are currently no diagnostic tests for RP, organ involvement is variable, and diagnosis is dependent on the identification of a pattern of clinical features that can be, at times, quite subtle. RP has a large impact on mortality and morbidity with a high rate of organ damage and resultant disability. Airway involvement can render patients with RP unable to communicate, struggling to breath, and dependent on a tracheostomy for survival. We started recruiting patients with RP to the NIH Clinical Center in August 2016. Since that time, we have evaluated 96 patients with a confirmed diagnosis of RP, with over 100 patients currently on the waiting list to be seen. All patients undergo comprehensive disease-specific clinical assessment including a detailed history and physical examination, audiometry, direct laryngoscopy, pulmonary function tests with oscillometry, and magnetic resonance imaging of the neck. In addition, we developed a novel method to perform dynamic computed tomography (CT) of the chest as a non-invasive way to detect structural damage to large airways. We anticipate that this cohort will be a rich source of clinical information for years to come as we begin to prospectively characterize this complex, heterogeneous disease. In addition to clinically profiling RP, we collect and bank biospecimens for use in future mechanistic studies. To date, our group published two patient-based online surveys in RP that describe a tremendous burden of disease and unmet need. We anticipate the first clinical and mechanistic reports from our group in RP within the next year. Deficiency of adenosine deaminase 2 (DADA2) is the first-ever reported monogenic form of systemic vasculitis. Reduction of adenosine deaminase 2 (ADA2) activity due to autosomal recessive loss-of-function mutations in the ADA2 gene results in a systemic form of vasculitis that resembles polyarteritis nodosa. Initial work into the underlying mechanisms of disease in DADA2 focused upon the skewed differentiation of monocytes towards pro-inflammatory macrophages in patients with DADA2. We recently published a study in Blood that characterizes a role for neutrophils in DADA2. We report for the first time ever that adenosine can trigger neutrophil extracellular traps (NETs) via engaging specific adenosine receptors on the surface of neutrophils. Genetic deficiency of ADA2 results in enhanced adenosine-mediated NET formation and subsequent TNF production in DADA2. In vivo evidence of NET formation in blood and tissue was demonstrated using samples from patients with DADA2 seen at the NIH Clinical Center. Novel pharmacologic inhibitors of specific adenosine receptors were developed for this project in collaboration with the laboratory of Kenneth Jacobson (NIDDK). A predilection for adenosine-mediated NET formation was seen when using neutrophils from female versus male patients. These results highlight a novel mechanism whereby adenosine, neutrophils, and macrophages interact to promote a pro-inflammatory environment in diseases like DADA2 and suggest that targeting specific pathways of adenosine metabolism may offer new therapeutic approaches in DADA2 and a broader spectrum of human inflammatory diseases.